World Small Animal Veterinary Association World Congress Proceedings, 2003

Jan Rothuizen

Professor of Internal Medicine, Department of Clinical Sciences of Companion Animals, University UtrechtUtrecht, The Netherlands

Copper toxicosis in Bedlington terriers has been the classical form of copper-associated hepatitis which is caused by a deletion in the Murr1 gene. Later on more breeds with such a high copper level in the lever that there was likely a primary copper-metabolic disease which caused hepatitis were: Bedlington terriers, Skye terriers, Dalmatians, West Highland White terriers and Turkish shepherds. Copper may also accumulate as a result of impaired biliary excretion secondary to cholestatic diseases. Therefore the question is hard to answer whether breed-associated forms of hepatitis in which copper is increased in the liver, the copper metabolism is primary or secondarily changed. The most prominent examples are hepatitis in Dobermans and Labrador retrievers. The best criteria to decide are threefold:

2. In all known primary copper metabolic disorders in dogs copper is accumulating in hepatocytes around the central vein (zone 3 of the liver lobule). In contrast, when cholestasis is the primary cause the accumulation of copper is less high and primarily localised in the portal tracts (zone 1 of the liver lobules).

3. If copper is the cause of the disease, a response to treatment with copper-chelating drugs like penicillamine or trientine is to be expected. Usually a three months treatment is necessary to see improvement or often complete recovery of the disease. If copper accumulation is secondary to cholestasis, there will be no response to chelation.

We have found arguments in categories 2 and 3, that hepatitis in many Labrador retrievers and Doberman Pinschers is in fact a primary disease of copper metabolism. Excessive copper is generally stored and encapsulated in the hepatocyte lysosomes. This encapsuled copper is not cytotoxic, and cannot be reached by chelating drugs. Since it is the free cytoplasmatic, and not the lysosomal copper which causes oxidative damage, quantitative copper measurements don't necessarily reflect the success of chelating or other therapy. This also implies that when copper is not stored in lysosomes, breeds with hepatitis and not so high copper can also have a primary copper metabolic disease. Therefore the criterium that copper should be in excess of 200 microgram/gram tissue in order to conclude to a primary role of copper, should be used with caution.

The increasing list of diseases in which hepatic copper accumulation may be the primary cause, indicates that specific therapies aimed at reducing free copper in the liver may become more important. But more importantly, molecular genetic methods to find new copper-associated genes in all the breeds mentioned before are expected to elucidate many new copper metabolic routes in the liver and other tissues. Only diseases in which copper accumulation is the primary defect need specific anti-copper medication. If copper accumulates as the consequence of a cholestatic disease, specific treatment of the underlying disease will reduce the amount of free cellular copper.

There are three forms of anti-copper medications for primary copper storage diseases. First, chelating drugs can actively bind free extracellular copper, upon which the complex is excreted into the urine by the kidneys. Extracellular copper exchanges with free intracellular copper, so that by constant exhaustion of the extracellular copper pool the toxic intracellular excess is also removed. There are two copper chelators available. D-penicillamine has also been widely used to treat Bedlington terriers with copper toxicosis. We have treated over 100 Bedlington terriers in which there was copper toxicosis without severe liver lesions yet, and found that it prevented the occurrence of clinical disease in all cases. The alternative copper chelating drugs which are 2,2,2- and 2-3-2-Tetramine tetrahydrochloride. Only the 2,2,2,-tetramine form (Trientine) is commercially available. Trientine may be more efficient in copper chelation than penicillamine, since copper deficiency as a result of chronic use has only been reported for Trientine. Both chelators are dosed at 10-15 mg/kg twice daily. Chelating drugs may have infrequent side effects, mainly nausea and vomiting. It is therefore preferred to give it twice daily together with meals.

The second medication is zinc, which can be given as the gluconate or acetate in capsules for oral use (10 mg elemental zinc/kg bid). In the intestinal tract zinc induces production of metallothionein in the enterocytes, which binds copper. The complex is sequestered with the senescent enterocytes into the feces. Zinc salts are given one hour before each meal, so that induction of metallothionein has taken place when alimentary copper is absorbed. The positive effect of zinc therapy has been evaluated critically in humans and has been reported anecdotally in dogs with copper storage disease.

In rare cases in which excessive copper causes haemolytic crisis it may be advisable to combine chelating drugs with anti-oxidants such as vitamin E.